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1.
Rev. lab. clín ; 12(3): e25-e39, jul.-sept. 2019. tab
Artigo em Espanhol | LILACS-Express | ID: ibc-ET1-4169

RESUMO

Varios miembros de diferentes asociaciones científicas y expertos de la reproducción han actualizado las recomendaciones de estudio genético e inmunológico en las parejas con disfunción en la reproducción con el fin de mejorar la asistencia sanitaria. El estudio se ha considerado altamente recomendable cuando la prueba diagnóstica es relevante para la toma de decisiones, moderada cuando estas han mostrado un resultado poco consistente y baja, cuando el beneficio de la prueba es incierto. Con la indicación de estas recomendaciones obtendremos una información relevante para el diagnóstico, pronóstico y tratamiento de la pareja con disfunción en la reproducción


In this article several members of diverse scientific associations and reproduction experts from Spain have updated different genetic and immunological procedure recommendations in couples affected by reproductive dysfunction with the goal of providing a set of useful guidelines for the clinic. The laboratory test has been considered as highly recommendable for making clinical decisions when the result of the diagnostic test is relevant, moderately recommendable when the results are of limited evidence because they are inconsistent, and low when the benefit of the test is uncertain. It is expected that these recommendations will provide some useful guidelines for the diagnosis, prognosis and treatment of couples presenting reproductive dysfunction

2.
Front Immunol ; 10: 654, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31001267

RESUMO

Background: The assessment of specific polysaccharide antibody production plays a pivotal role in the diagnosis of humoral primary immunodeficiencies (PID). The response to 23-valent pneumococcal vaccine (PPV) remains the gold standard for the diagnosis of polysaccharide antibodies. However, in Spain, the interpretation of pure polysaccharide 23-valent immunization is hampered by the high endemicity of pneumococcal disease and the generalization of the 13-valent adjuvant pneumococcal vaccination. Specific Typhim Vi vaccination (TV) immunoglobulin G IgG response to immunization is useful in adult PID, but there is no data regarding children. Objectives: To evaluate the clinical utility of TV IgG production as a diagnostic tool to determine anti-polysaccharide antibody production deficiency in children, when the response to PPV is unclear and isolated determination of serotypes is unfeasible. Methods: We conducted a single-institution prospective observational study on 61 children with recurrent infections. Baseline specific antibodies against PPV and TV were evaluated. In 28 children (46%), the response to the production of antibodies confirmed a clinical suspicion of humoral PID, and they were therefore immunized with 23-valent pneumococcal vaccine and Typhim Vi. Both specific antibody responses were measured by ELISA (The Binding Site Group Ltd, Birmingham, UK) using previously published cut-offs. Results: Seventy percent of the 61 children displayed baseline PPV IgG > 27 mg/L, whereas only 8% showed TV IgG > 28 U/mL (p < 0.0001). Twenty-one of 28 children (75%) achieved a 3-fold increase in post-vaccination TV IgG levels, whereas only 3% achieved a 4-fold increase in PPV IgG post vaccination, mainly due to high baseline PPV IgG titers. When we classified children according to their response to TV as responders or non-responders and compared this with the well-known clinical warning signs of the Jeffrey Modell Foundation. The proportions of children with history of pneumonia and the need for intravenous antibiotics were significantly higher in TV IgG non-responders than in TV IgG responders (p = 0.02 and p = 0.01, respectively). Conclusion: Response to TV can be considered an ancillary diagnostic tool to determine polysaccharide antibodies in children, particularly when isolated determination of pneumococcal serotypes is not feasible. TV provides a useful asset for clinicians in the era of conjugate PPV vaccination, with clinical relevance. Further research is warranted for validation.

3.
Front Cell Neurosci ; 13: 107, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941020

RESUMO

Antiphospholipid syndrome (APS) is characterized by arterial and venous thrombosis, pregnancy morbidity and fetal loss caused by pathogenic autoantibodies directed against phospholipids (PL) and PL-cofactors. Isolated neurological APS may represent a significant diagnostic challenge, as epidemiological, clinical and neuroimaging features may overlap with those of multiple sclerosis (MS). In an open view, MS could be considered as an organ-specific anti-lipid (phospholipid and glycosphingolipid associated proteins) disease, in which autoreactive B cells and CD8+ T cells play a dominant role in its pathophysiology. In MS, diverse autoantibodies against the lipid-protein cofactors of the myelin sheath have been described, whose pathophysiologic role has not been fully elucidated. We carried out a review to select clinical studies addressing the prevalence of antiphospholipid (aPL) autoantibodies in the so-called MS-like syndrome. The reported prevalence ranged between 2% and 88%, particularly aCL and aß2GPI, with predominant IgM isotype and suggesting worse MS prognosis. Secondarily, an updated summary of current knowledge on the pathophysiological mechanisms and events responsible for these conditions is presented. We draw attention to the clinical relevance of diagnosing isolated neurological APS. Prompt and accurate diagnosis and antiaggregant and anticoagulant treatment of APS could be vital to prevent or at least reduce APS-related morbidity and mortality.

4.
Front Immunol ; 10: 586, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984175

RESUMO

Background: Immunodeficiencies (ID), in particular primary immunodeficiencies (PID), are often associated with haematological manifestations, such as peripheral cytopenias or lymphoproliferative syndromes. Early diagnosis and management have significant prognostic implications. Secondary immunodeficiencies (SID) may also be induced by oncohaematological diseases and their treatments. Haematologists and oncologists must therefore be aware of the association between blood disorders and cancer and ID, and be prepared to offer their patients appropriate treatment without delay. Our aim was to define the warning signs of primary and secondary IDs in paediatric and adult patients with oncohaematological manifestations. Methods: A multidisciplinary group of six experts (2 haematologists, 2 immunologists, and 2 paediatricians specializing in ID) conducted a literature review and prepared a document based on agreements reached an in-person meeting. An external group of 44 IDs specialists from all over Spain assessed the document and were consulted regarding their level of agreement. Results: This document identifies the haematological and extra-haematological diseases that should prompt a suspicion of PIDs in adults and children, in both primary care and haematology and oncology departments. Cytopenia and certain lymphoproliferative disorders are key diagnostic pointers. The diagnosis must be based on a detailed clinical history, physical exploration, complete blood count and standard laboratory tests. The immunological and haematological tests included in the diagnostic process will depend on the care level. Patients who are candidates for immunoglobulin replacement therapy must be carefully selected, and treatment should be offered as soon as possible to avoid the development of complications. Finally, this document recommends procedures for monitoring these patients. Conclusions: This document combines scientific evidence with the opinion of a broad panel of experts, and emphasizes the importance of an early diagnosis and treatment to avoid complications. The resulting document is a useful tool for primary care physicians and specialists who see both adult and paediatric patients with oncohaematological diseases.

5.
Eur J Haematol ; 102(6): 447-456, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30801785

RESUMO

OBJECTIVE: Despite long-standing safe and effective use of immunoglobulin replacement therapy (IgRT) in primary immunodeficiency, clinical data on IgRT in patients with secondary immunodeficiency (SID) due to B-cell lymphoproliferative diseases are limited. Here, we examine the correlation between approved IgRT indications, treatment recommendations, and clinical practice in SID. METHODS: An international online survey of 230 physicians responsible for the diagnosis of SID and the prescription of IgRT in patients with hematological malignancies was conducted. RESULTS: Serum immunoglobulin was measured in 83% of patients with multiple myeloma, 76% with chronic lymphocytic leukemia, and 69% with non-Hodgkin lymphoma. Most physicians (85%) prescribed IgRT after ≥2 severe infections. In Italy, Germany, Spain, and the United States, immunoglobulin use was above average in patients with hypogammaglobulinemia, while in the UK considerably fewer patients received IgRT. The use of subcutaneous immunoglobulin was highest in France (34%) and lowest in Spain (19%). Immunologists measured specific antibody responses, performed test immunization, implemented IgRT, and used subcutaneous immunoglobulin more frequently than physicians overall. CONCLUSIONS: The management of SID in hematological malignancies varied regionally. Clinical practice did not reflect treatment guidelines, highlighting the need for robust clinical studies on IgRT in this population and harmonization between countries and disciplines.


Assuntos
Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/epidemiologia , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/etiologia , Gerenciamento Clínico , Saúde Global , Humanos , Imunoglobulinas/sangue , Imunoglobulinas/imunologia , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/terapia , Controle de Infecções , Vigilância em Saúde Pública , Resultado do Tratamento
7.
Reumatol Clin ; 2018 Dec 06.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30527360

RESUMO

An urgent search is currently underway for alternatives to antibiotics to prevent infections, due to the accelerated evolution and increase in antibiotic resistance. This problem is more serious for patients with recurrent infections, since they have to use many cycles of antibiotics per year, so the risk for antibiotic resistance is higher and can be life-threatening. In recent years, the use of prophylactic vaccines via the mucosal route for these patients with recurrent infections has been demonstrated as a potentially beneficial and safe alternative to prevent infections. The new knowledge about mucosal immunity and trained immunity, a form of innate immunity memory that can enhance the response to different infectious threads, has made it easier to extend its use. The application of the new concepts of trained immunity may explain the simultaneous pro-tolerogenic and boosting effect or effects of these drugs on diverse immune cells for different infections. In this review, we describe the immunomodulatory mechanisms of mucosal polybacterial vaccines and their connection with trained immunity and its utility in the prevention of recurrent infections in immunosuppressed patients.

8.
Respir Res ; 19(1): 219, 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30419907

RESUMO

BACKGROUND: Pulmonary complications are common in primary immunodeficiency diseases (PID) and contribute to morbidity and mortality in these patients. However, their varied presentation and a general lack of awareness of PID in this setting make early diagnosis and treatment difficult. The aim of this study was to define the warning signs of PID in patients with respiratory manifestations, the necessary diagnostic tests, and the therapeutic management of both children and adults. METHODS: A review of the literature was performed, and 43 PID interdisciplinary specialists were consulted. RESULTS: This document identifies the pulmonary and extrapulmonary manifestations that should prompt a suspicion of PID, the immunological and respiratory tests that should be included in the diagnostic process according to the level of care, recommendations regarding the use of immunoglobulin replacement therapy according to the specific immunodeficiency, and the minimum recommended immunological and pulmonary monitoring in these patients. CONCLUSIONS: This document is the first to combine scientific evidence with the opinion of a broad panel of experts specializing in the treatment of patients with immunodeficiencies. It aims to provide a useful tool for all practitioners who are regularly involved in the management of these patients.


Assuntos
Gerenciamento Clínico , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/terapia , Pneumopatias/diagnóstico , Pneumopatias/terapia , Prova Pericial/métodos , Prova Pericial/tendências , Humanos , Síndromes de Imunodeficiência/epidemiologia , Pneumopatias/epidemiologia
9.
Med. clín (Ed. impr.) ; 151(4): 161.e1-161.e12, ago. 2018. tab
Artigo em Espanhol | IBECS | ID: ibc-173869

RESUMO

Varios miembros de diferentes asociaciones científicas y expertos de la reproducción han actualizado las recomendaciones de estudio genético e inmunológico en las parejas con disfunción en la reproducción con el fin de mejorar la asistencia sanitaria. El estudio se ha considerado altamente recomendable cuando la prueba diagnóstica es relevante para la toma de decisiones, moderada cuando estas han mostrado un resultado poco consistente y baja, cuando el beneficio de la prueba es incierto. Con la indicación de estas recomendaciones obtendremos una información relevante para el diagnóstico, pronóstico y tratamiento de la pareja con disfunción en la reproducción


In this article several members of diverse scientific associations and reproduction experts from Spain have updated different genetic and immunological procedure recommendations in couples affected by reproductive dysfunction with the goal of providing a set of useful guidelines for the clinic. The laboratory test has been considered as highly recommendable for making clinical decisions when the result of the diagnostic test is relevant, moderately recommendable when the results are of limited evidence because they are inconsistent, and low when the benefit of the test is uncertain. It is expected that these recommendations will provide some useful guidelines for the diagnosis, prognosis and treatment of couples presenting reproductive dysfunction


Assuntos
Humanos , Masculino , Feminino , Reprodução/genética , Obtenção de Tecidos e Órgãos/métodos , Reprodução/imunologia , Prognóstico , Reprodução/ética , Infertilidade Masculina/genética , Epigênese Genética
10.
Therap Adv Gastroenterol ; 11: 1756284818783613, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30034528

RESUMO

Background: The aim of this study was to evaluate reliability of four different assays for measuring infliximab trough levels and antibodies to infliximab (ATI). Methods: In this non-interventional, cross-sectional study including IBD patients, infliximab levels and ATI were measured using four different assays: Lisa-Tracker, Promonitor, Q-Inflixi and Sanquin. Reliability and agreement for infliximab levels was assessed using the intraclass correlation coefficient (ICC) and Bland-Altman plots. Qualitative agreement for infliximab (based on a pre-established target window of trough levels between 3 µg/ml and 7 µg/ml) and for ATI were estimated by Cohen's kappa. Results: Serum samples of 84 IBD patients were evaluated for infliximab using the four assays. Reliability was 'substantial' between Lisa-Tracker versus Promonitor and 'almost perfect' between the remaining assay pairs, with ICCs [95% confidence interval (CI)] ranging from 0.93 (0.70-0.97) for Lisa-Tracker versus Promonitor to 0.97 (0.95-0.98) for Q-Inflixi versus Sanquin. Bland-Altman plots showed significant bias between assays except Promonitor versus Q-Inflixi, which had excellent agreement. The greatest differences in mean infliximab were found between Promonitor versus Lisa-Tracker (-0.91 µg/ml) and Lisa-Tracker versus Q-Inflixi (0.69 µg/ml). Qualitative agreement for infliximab was 'almost perfect' for Promonitor versus Q-Inflixi (kappa 0.84) and Q-Inflixi versus Sanquin (kappa 0.81), and 'substantial' for the remaining pairs. More than 10% of patients who had infliximab levels within the target interval by Lisa-Tracker had suboptimal concentrations (<3 µg/ml) with Promonitor and Q-Inflixi. Furthermore, 11% of patients within the target interval by Q-Inflixi had supra-optimal levels (>7 µg/ml) by Lisa-Tracker. In the remaining paired comparisons, fewer than 5% of patients were placed in different subgroups. Qualitative agreement for ATI fluctuated between 'moderate' and 'almost perfect'. Conclusions: All four assays seem suitable for therapeutic drug monitoring of infliximab. Promonitor and Q-Inflixi had the best agreement, making those assays fully interchangeable. Systematic biases between Lisa-Tracker with Promonitor and Q-Inflixi suggest that these assays should not be interchanged during the follow up of an individual patient.

11.
Front Immunol ; 9: 1328, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29951065

RESUMO

Lenalidomide is an analog of thalidomide, with potent anticancer activity demonstrated in several hematological malignancies. It has immunomodulatory properties, being able to enhance the activation of different types of immune cells, which results in antitumor activities. Dendritic cells (DCs) are pivotal in the immune response, and different immunotherapeutic approaches targeting these cells are being developed. Since little is known about the effect of lenalidomide on DCs, the goal of the present work was to investigate the phenotype and function of human monocyte-derived DCs differentiated in the presence of lenalidomide (L-DCs). Our results showed that L-DCs display a unique phenotype, with increased cell surface expression of some maturation markers such as CD1d, CD83, CD86, and HLA-DR. This phenotype correlates with a lower expression of the E3 ubiquitin-ligase MARCH-I in L-DCs, upregulating the cell surface expression of CD86 and HLA-DR. In addition, immature L-DCs express higher amounts of DC-SIGN on the cell surface than control immature DCs. After LPS stimulation, production of IL-6 and TNF-α was severely decreased, whereas IL-12 and IL-10 secretion was dramatically upregulated in L-DCs, compared to that in the controls. Functionally, L-DCs are more effectively recognized by NKT cells in cytotoxicity experiments. Furthermore, L-DCs display higher opsonin-independent antigen uptake capability than control DCs. Mixed lymphocyte reaction experiments showed that L-DCs could stimulate naïve CD4 T-cells, polarizing them toward a predominant Th1 phenotype. In summary, DCs derived from monocytes in the presence of lenalidomide present a semi-mature phenotype, increased phagocytic capacity, reduced production of proinflammatory cytokines, and the ability to polarize T-cells toward predominant Th1-type responses; these are qualities that might be useful in the development of new immunotherapeutic treatments.

12.
Front Immunol ; 9: 1240, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29915590

RESUMO

Background: Multiple sclerosis (MS) is a chronic, progressive autoimmune disease of the central nervous system in which inflammation plays a key role in the induction, development, and progression. Most of the MS patients present with relapsing-remitting (RR) form, characterized by flare-ups followed by periods of recovery. Many inflammatory and anti-inflammatory cytokines have been proposed as backers in MS pathogenesis, and the balance between these differing cytokines can regulate MS severity. Interferon (IFN)-ß, a current disease-modifying therapy for MS, has demonstrated beneficial effects in reducing disease severity in MS patients. However, its immunoregulatory and anti-inflammatory actions in MS are not wholly understood. The aim of the study was to define, in clinically stable patients with RR-MS, the serum concentration of several cytokines, canonical or not, and their modulation by IFN-ß therapy. Methods: Relapsing-remitting-MS patients were enrolled and diagnosed according to revised Mc Donald Diagnostic Criteria. A set of cytokines [including non-canonical neurotransmitter acetylcholine (ACh) and adipokines] and B-cell differentiation molecules, as potential biomarkers, were evaluated in 30 non-treated RR-MS patients compared to 30 IFN-ß-treated MS patients and 30 age, gender, and body mass index-matched healthy controls (HC). Results: Naïve MS patients showed significantly higher levels of interleukin (IL)-1ß, IL-12/IL-23p40, IL-18, high-mobility group box protein-1, and IL-18 binding protein (IL-18BP) than MS-treated patients (p < 0.001 for all) and HC (p < 0.01). IFN-ß therapy has significantly downmodulated IL-1ß, IL-12/IL-23p40, IL-18 to normal levels (p < 0.001), whereas it has decreased IL-18BP (p < 0.001). ACh was significantly higher in the IFN-ß-treated than HC and non-treated MS patients (p < 0.001). No significant differences were observed either in adipokines concentration or in B-cell-associated molecules among the three study groups. Conclusion: Although more experimental evidence are required, we speculate that the efficacy of treatment of MS with IFN-ß is mediated, at least in part, by its ability to work on several levels to slow down the disease progression. Proposed actions include the modulation of IL-1-inflammasome axis and modulation of ACh, B-cell activating factor/a proliferation-inducing ligand system, and several adipokines.


Assuntos
Biomarcadores , Citocinas/sangue , Esclerose Múltipla Recidivante-Remitente/sangue , Adulto , Idoso , Estudos de Casos e Controles , Pessoas com Deficiência , Feminino , Humanos , Inflamassomos , Mediadores da Inflamação/metabolismo , Interferon beta/uso terapêutico , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/terapia , Índice de Gravidade de Doença
13.
J Immunol ; 201(1): 41-52, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29743313

RESUMO

IVIg is an approved therapy for immunodeficiency and for several autoimmune and inflammatory diseases. However, the molecular basis for the IVIg anti-inflammatory activity remains to be fully explained and cannot be extrapolated from studies on animal models of disease. We now report that IVIg impairs the generation of human monocyte-derived anti-inflammatory macrophages by inducing JNK activation and activin A production and limits proinflammatory macrophage differentiation by inhibiting GM-CSF-driven STAT5 activation. In vivo, IVIg provokes a rapid increase in peripheral blood activin A, CCL2, and IL-6 levels, an effect that can be recapitulated in vitro on human monocytes. On differentiating monocytes, IVIg promotes the acquisition of altered transcriptional and cytokine profiles, reduces TLR expression and signaling, and upregulates negative regulators of TLR-initiated intracellular signaling. In line with these effects, in vivo IVIg infusion induces a state tolerant toward subsequent stimuli that results in reduced inflammatory cytokine production after LPS challenge in human peripheral blood and significant protection from LPS-induced death in mice. Therefore, IVIg conditions human macrophages toward the acquisition of a state of cross-tolerance against inflammatory stimuli, an effect that correlates with the net anti-inflammatory action of IVIg in vivo.


Assuntos
Anti-Inflamatórios/imunologia , Tolerância Imunológica/imunologia , Imunoglobulinas Intravenosas/imunologia , Imunoglobulinas Intravenosas/farmacologia , Macrófagos/imunologia , Fator de Transcrição STAT5/metabolismo , Ativinas/sangue , Animais , Células Cultivadas , Quimiocina CCL2/sangue , Ativação Enzimática , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Inflamação/imunologia , Interleucina-6/sangue , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lipopolissacarídeos/imunologia , Camundongos , Monócitos/citologia , Monócitos/imunologia
14.
J Immunol Methods ; 459: 1-10, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29800575

RESUMO

Response to polysaccharide vaccination can be an invaluable tool for assessing functionality of the adaptive immune system. Measurement of antibodies raised in response to Pneumovax®23 is the current gold standard test, but there are significant challenges and constraints in both the measurement and interpretation of the response. An alternative polysaccharide vaccine approach (Salmonella typhi Vi capsule (ViCPS)) has been suggested. In the present article, we review current evidence for the measurement of ViCPS antibodies in the diagnosis of primary and secondary antibody deficiencies. In particular, we review emerging data suggesting their interpretation in combination with the response to Pneumovax®23 and comment upon the utility of these vaccines to assess humoral immune responses while receiving immunoglobulin replacement therapy (IGRT).


Assuntos
Imunidade Adaptativa , Anticorpos Antibacterianos/sangue , Polissacarídeos Bacterianos/imunologia , Salmonella typhi/imunologia , Febre Tifoide/imunologia , Vacinas Tíficas-Paratíficas/imunologia , Animais , Anticorpos Antibacterianos/imunologia , Ensaios Clínicos como Assunto , Humanos , Imunização Passiva , Síndromes de Imunodeficiência , Camundongos , Vacinas Pneumocócicas/imunologia , Testes Sorológicos , Febre Tifoide/diagnóstico
15.
Med Clin (Barc) ; 151(4): 161.e1-161.e12, 2018 08 22.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-29680457

RESUMO

In this article several members of diverse scientific associations and reproduction experts from Spain have updated different genetic and immunological procedure recommendations in couples affected by reproductive dysfunction with the goal of providing a set of useful guidelines for the clinic. The laboratory test has been considered as highly recommendable for making clinical decisions when the result of the diagnostic test is relevant, moderately recommendable when the results are of limited evidence because they are inconsistent, and low when the benefit of the test is uncertain. It is expected that these recommendations will provide some useful guidelines for the diagnosis, prognosis and treatment of couples presenting reproductive dysfunction.


Assuntos
Infertilidade Feminina/genética , Infertilidade Feminina/imunologia , Infertilidade Masculina/genética , Infertilidade Masculina/imunologia , Aberrações Cromossômicas , Concepção de Doadores/normas , Epigênese Genética , Feminino , Doenças Genéticas Inatas/diagnóstico , Testes Genéticos/classificação , Testes Genéticos/normas , Humanos , Masculino , Reprodução/ética , Fatores Sexuais
16.
Int J Cancer ; 142(1): 133-144, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28884480

RESUMO

Human blood monocytes are very potent to take up antigens. Like macrophages in tissue, they efficiently degrade exogenous protein and are less efficient than dendritic cells (DCs) at cross-presenting antigens to CD8+ T cells. Although it is generally accepted that DCs take up tissue antigens and then migrate to lymph nodes to prime T cells, the mechanisms of presentation of antigens taken up by monocytes are poorly documented so far. In the present work, we show that monocytes loaded in vitro with MelanA long peptides retain the capacity to stimulate antigen-specific CD8+ T cell clones after 5 days of differentiation into monocytes-derived dendritic cells (MoDCs). Tagged-long peptides can be visualized in electron-dense endocytic compartments distinct from lysosomes, suggesting that antigens can be protected from degradation for extended periods of time. To address the pathophysiological relevance of these findings, we screened blood monocytes from 18 metastatic melanoma patients and found that CD14+ monocytes from two patients effectively activate a MelanA-specific CD8 T cell clone after in vitro differentiation into MoDCs. This in vivo sampling of tumor antigen by circulating monocytes might alter the tumor-specific immune response and should be taken into account for cancer immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Apresentação Cruzada/imunologia , Células Dendríticas/imunologia , Antígeno MART-1/imunologia , Melanoma/imunologia , Monócitos/imunologia , Apresentação do Antígeno/imunologia , Diferenciação Celular/imunologia , Células Dendríticas/citologia , Humanos , Monócitos/citologia
17.
Eur J Immunol ; 48(1): 180-193, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28799230

RESUMO

Recurrent respiratory tract infections (RRTIs) are the first leading cause of community- and nosocomial-acquired infections. Antibiotics remain the mainstay of treatment, enhancing the potential to develop antibiotic resistances. Therefore, the development of new alternative approaches to prevent and treat RRTIs is highly demanded. Daily sublingual administration of the whole heat-inactivated polybacterial preparation (PBP) MV130 significantly reduced the rate of respiratory infections in RRTIs patients, however, the immunological mechanisms of action remain unknown. Herein, we study the capacity of MV130 to immunomodulate the function of human dendritic cells (DCs) as a potential mechanism that contribute to the clinical benefits. We demonstrate that DCs from RRTIs patients and healthy controls display similar ex vivo immunological responses to MV130. By combining systems biology and functional immunological approaches we show that MV130 promotes the generation of Th1/Th17 responses via receptor-interacting serine/threonine-protein kinase-2 (RIPK2)- and myeloid-differentiation primary-response gene-88 (MyD88)-mediated signalling pathways under the control of IL-10. In vivo BALB/c mice sublingually immunized with MV130 display potent systemic Th1/Th17 and IL-10 responses against related and unrelated antigens. We elucidate immunological mechanisms underlying the potential way of action of MV130, which might help to design alternative treatments in other clinical conditions with high risk of recurrent infections.


Assuntos
Vacinas Bacterianas/imunologia , Células Dendríticas/imunologia , Interleucina-10/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Infecções Respiratórias/prevenção & controle , Células Th1/imunologia , Células Th17/imunologia , Adulto , Idoso , Animais , Células Cultivadas , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Infecções Respiratórias/imunologia , Infecções Respiratórias/microbiologia , Transdução de Sinais/imunologia
18.
Front Immunol ; 9: 2936, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30619296

RESUMO

Challenge with specific microbial stimuli induces long lasting epigenetic changes in innate immune cells that result in their enhanced response to a second challenge by the same or unrelated microbial insult, a process referred to as trained immunity. This opens a new avenue in vaccinology to develop Trained Immunity-based Vaccines (TIbV), defined as vaccine formulations that induce training in innate immune cells. Unlike conventional vaccines, which are aimed to elicit only specific responses to vaccine-related antigens, TIbV aim to stimulate broader responses. As trained immunity is generally triggered by pattern recognition receptors (PRRs), TIbV should be formulated with microbial structures containing suitable PRR-ligands. The TIbV concept we describe here may be used for the development of vaccines focused to promote host resistance against a wide spectrum of pathogens. Under the umbrella of trained immunity, a broad protection can be achieved by: (i) increasing the nonspecific effector response of innate immune cells (e.g., monocyte/macrophages) to pathogens, (ii) harnessing the activation state of dendritic cells to enhance adaptive T cell responses to both specific and nonrelated (bystander) antigens. This capacity of TIbV to promote responses beyond their nominal antigens may be particularly useful when conventional vaccines are not available or when multiple coinfections and/or recurrent infections arise in susceptible individuals. As the set of PRR-ligands chosen is essential not only for stimulating trained immunity but also to drive adaptive immunity, the precise design of TIbV will improve with the knowledge on the functional relationship among the different PRRs. While the TIbV concept is emerging, a number of the current anti-infectious vaccines, immunostimulants, and even vaccine adjuvants may already fall in the TIbV category. This may apply to increase immunogenicity of novel vaccine design approaches based on small molecules, like those achieved by reverse vaccinology.


Assuntos
Memória Imunológica , Controle de Infecções/métodos , Receptores de Reconhecimento de Padrão/imunologia , Vacinas/imunologia , Imunidade Adaptativa , Adjuvantes Imunológicos/uso terapêutico , Humanos , Imunidade Inata , Imunogenicidade da Vacina , Vacinas/uso terapêutico
19.
Front Cell Neurosci ; 11: 340, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29163052

RESUMO

The recognition of internal and external sources of stimuli, the self from non-self, seems to be an intrinsic property to the adequate functioning of the immune system and the nervous system, both complex network systems that have evolved to safeguard the self biological identity of the organism. The mammalian brain development relies on dynamic and adaptive processes that are now well described. However, the rules dictating this highly constrained developmental process remain elusive. Here we hypothesize that there is a cellular basis for brain selfhood, based on the analogy of the global mechanisms that drive the self/non-self recognition and instruction by the immune system. In utero education within the thymus by multi-step selection processes discard overly low and high affinity T-lymphocytes to self stimuli, thus avoiding expendable or autoreactive responses that might lead to harmful autoimmunity. We argue that the self principle is one of the chief determinants of neocortical brain neurogenesis. According to our hypothesis, early-life education on self at the subcortical plate of the neocortex by selection processes might participate in the striking specificity of neuronal repertoire and assure efficiency and self tolerance. Potential implications of this hypothesis in self-reactive neurological pathologies are discussed, particularly involving consciousness-associated pathophysiological conditions, i.e., epilepsy and schizophrenia, for which we coined the term autophrenity.

20.
Int J Mol Sci ; 18(6)2017 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-28635659

RESUMO

Asthma is an airway disease characterised by chronic inflammation with intermittent or permanent symptoms including wheezing, shortness of breath, chest tightness, and cough, which vary in terms of their occurrence, frequency, and intensity. The most common associated feature in the airways of patients with asthma is airway inflammation. In recent decades, efforts have been made to characterise the heterogeneous clinical nature of asthma. The interest in improving the definitions of asthma phenotypes and endotypes is growing, although these classifications do not always correlate with prognosis nor are always appropriate therapeutic approaches. Attempts have been made to identify the most relevant molecular and cellular biomarkers underlying the immunopathophysiological mechanisms of the disease. For almost 50 years, immunoglobulin E (IgE) has been identified as a central factor in allergic asthma, due to its allergen-specific nature. Many of the mechanisms of the inflammatory cascade underlying allergic asthma have already been elucidated, and IgE has been shown to play a fundamental role in the triggering, development, and chronicity of the inflammatory responses within the disease. Blocking IgE with monoclonal antibodies such as omalizumab have demonstrated their efficacy, effectiveness, and safety in treating allergic asthma. A better understanding of the multiple contributions of IgE to the inflammatory continuum of asthma could contribute to the development of novel therapeutic strategies for the disease.


Assuntos
Antiasmáticos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Asma/tratamento farmacológico , Imunoglobulina E/imunologia , Omalizumab/uso terapêutico , Animais , Asma/imunologia , Asma/fisiopatologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/fisiopatologia
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